1. Small-molecule BCL6 inhibitor effectively treats mice with nonsclerodermatous chronic graft-versus-host disease.
- Author
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Paz K, Flynn R, Du J, Qi J, Luznik L, Maillard I, MacDonald KP, Hill GR, Serody JS, Murphy WJ, Sage PT, Sharpe AH, Miklos D, Cutler CS, Koreth J, Antin JH, Soiffer RJ, Ritz J, Bradner JE, Melnick AM, and Blazar BR
- Subjects
- Animals, B-Lymphocytes drug effects, B-Lymphocytes metabolism, Bronchiolitis Obliterans immunology, Bronchiolitis Obliterans pathology, Chronic Disease, Germinal Center metabolism, Germinal Center pathology, Graft vs Host Disease etiology, Graft vs Host Disease pathology, Lymphocyte Activation immunology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, T-Lymphocytes drug effects, T-Lymphocytes metabolism, T-Lymphocytes, Helper-Inducer drug effects, T-Lymphocytes, Helper-Inducer immunology, T-Lymphocytes, Helper-Inducer metabolism, B-Lymphocytes immunology, Bronchiolitis Obliterans complications, Germinal Center drug effects, Graft vs Host Disease drug therapy, Proto-Oncogene Proteins c-bcl-6 physiology, Small Molecule Libraries pharmacology, T-Lymphocytes immunology
- Abstract
Patient outcomes for steroid-dependent or -refractory chronic graft-versus-host diesease (cGVHD) are poor, and only ibrutinib has been US Food and Drug Administration (FDA) approved for this indication. cGVHD is often driven by the germinal center (GC) reaction, in which T follicular helper cells interact with GC B cells to produce antibodies that are associated with disease pathogenesis. The transcriptional corepressor B-cell lymphoma 6 (BCL6) is a member of the Broad-complex, Tramtrack, and Bric-abrac/poxvirus and zinc finger (BTB/POZ) transcription factor family and master regulator of the immune cells in the GC reaction. We demonstrate that BCL6 expression in both donor T cells and B cells is necessary for cGVHD development, pointing to BCL6 as a therapeutic cGVHD target. A small-molecule BCL6 inhibitor reversed active cGVHD in a mouse model of multiorgan system injury with bronchiolitis obliterans associated with a robust GC reaction, but not in cGVHD mice with scleroderma as the prominent manifestation. For cGVHD patients with antibody-driven cGVHD, targeting of BCL6 represents a new approach with specificity for a master GC regulator that would extend the currently available second-line agents., (© 2019 by The American Society of Hematology.)
- Published
- 2019
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